Age-related changes in the male reproductive tract are of importance for a number of reasons, including: 1) the population of the United States is aging rapidly; 2) a number of diseases of aged men, such as benign prostatic hyperplasia and prostatic cancer, depend upon testicular hormones; 3) other endocrine diseases such as osteoporosis, are likely to become major problems in geriatric males; 4) age-related changes in drug and xenobiotic effects have been shown; and 5) couples are waiting until later in life to have children, making it increasingly important to understand the relationship of age to the production of adequate numbers of fertile, genetically competent spermatozoa. The male reproductive tract offers many advantages for studies of age- related phenomena, including: 1) experimental manipulation of the testes/epididymides is unlikely to cause death or morbidity; 2) much is known about the regulation of the male tract; and 3) the male reproductive system is an excellent model for generalized aging because it is possible to study, at once, the influence of age on cells that have different proliferative capacities and are different stages of differentiation. Thus, there are cells that are proliferating rapidly by mitosis (spermatogonia, prostatic epithelial cells), undergoing meiosis (spermatocytes), permanently postreplicative (Sertoli cells), slowly turning over (Leydig cells), differentiating (spermatids), terminally differentiated (spermatozoa), and exquisitely sensitive to hormones and to changes in testicular function (epididymal and prostatic epithelial cells). In the rat, as in the human, striking changes occur with aging of the male reproductive tract, including reduced secretion of testosterone, diminished germ cell production, reduced numbers of testicular and epididymal spermatozoa, atrophy of the seminiferous epithelium, and increased sensitivity of the prostate gland to androgens. The major objectives of this program project application are to elucidate the critical structural and functional changes associated with aging of Leydig, Sertoli and epididymal cells, and to determine the mechanisms by which such changes occur.